Oxido-steroids and process for their manufacture



such as are obtained,

United States Patent 18 Claims. (Cl. 260-23955) This invention relatesto a process for the manufacture of lzlla-oxido steroids and theirconversion products. lrlla-oxido steroids have not so far been describedin the literature. This class of new compounds is of particular interestbecause opening of the oxide ring under certain conditions results inthe formation of l-dehydro-llot-hydroxy steroids, which constitutes anew approach to the therapeutically important l-dehydro-corticoids, suchas prednisone, prednisolone, l-dehydro-aldosterone, dexamethasone, or tol-dehydro-testosterone derivatives, such as thel-dehydro-l7a-methyl-testosterone which has an anabolic action.

The process of the present invention consists in treating anlla-hydroxy-steroid, which contains no free hydroxyl group in position20, with acyloxy radicals having an oxidising action and, if desired, inthe resulting lzllot-oxidosteroid the oxido group is opened up bytreatment with an acid or, after formation of an 0x0 group in position3, also by treatment with a base.

The conversion according to the present process of thelle-hydroxy-steroids into lzlla-oxido-steroids can be carried out withacyloxy radicals having oxidising action more especially, by splittingmetal acylates. Among the metal acylates may be mentioned moreespecially those of tetravalent lead in which the acyl radical ispreferably derived from a lower aliphatic or aromatic acid, for examplelead tetraacetate, lead tetrapropionate, lead tetrabutyrate, leadtetrabenzoate and the like. Likewise suitable are the complexes ofmercury acylates and silver acylates such as mercury acetate, silveracetate or silver benzoate with iodine. The reaction is performed in asuitable solvent which is inert to the oxidising agent, such ashydrocarbons for example benzene. hydrocarbons such as The process isadvantageously performed at a temperature ranging from 50 to 150 C., butit can also be carried out at a temperature above or below this range.

Compounds suitable as starting materials for the present process areIla-hydroxy compounds of the cholestane,

acid, phenylpropionic acid, aliphatic or aromatic heterocyclic acids,such as furan carboxylic acid, nicotinic acid or also of sulfonic acids,such as methane sulfonic acid, benzenesulfonic, paratoluene sulfonicacid or the like. In the ethers the alcoholic radical is preferably onederived from a lower aliphatic'alcohol, such as methyl, ethyl, propyl,butyl, isopropyl, isobutyl alcohol or of an araliphatic alcohol, such asa monocyclic lower araliphatic alcohol e.g. 'benzyl alcohol or ofheterocyclic alcohols, such as tetrahydropyranol or the like. Among thecompounds having ketalized or acetalized oxo groups there are especiallyto be mentioned those which have oxo groups ketalized or acetalized witha lower divalent aliphatic alcohol, such as ethylene glycol, propyleneglycol and the like. Furthermore, the starting materials may containdouble bonds, for example, starting from carbon atom 5. Examples ofspecific starting materials are 3 B-acyloxy-l la-hydroxy-cholestane,

l 1ot-hydroxy-tigogenine acylates,

l lwhydroxy-diosgenine acylates,

sarmentogenine-3-acetate,

3ot-acyloxy-1lot-hydroxy-ZO-ethylenedioxy-S/B-pregnane,

3B-acyloxy-l 1a-hydroxy-20-ethylenedioxy-Sa-pregnane,

A -3B-acyloxy-1 1 a-hydrOXy-ZO-ethylenedioxy-pregnene,

A -3 :20-bis-ethylenedioxy-1 l ot-hydroxy-pregnene,

A -3 ZO-bisethylene-dioxy-l 1a-hydroxy-21 -acyloxypregnene,

A -3 :ZO-bisethylene-dioxy-l la: l7a-dihydroxy-2lacyloxy-pregnene,

A -3,B: l7B-diacyloxy-l la-hydroxy-androstene,

3 B: l7B-diacyloxy-l la-hydroxy-5a-androstane,

A -3-ethylenedioxy-l lwhydroxy- 1 7fi-acyloxy-androstene,

A -3-ethylenedioxy-l lot-hydroxy-l7,8-acyloxy-17amethyl-androstene,

A -3 l7-bisethylenedioxy-1 lu-hydroxy-amdrostene,

A -3-ethylenedioxy-1 la-hydroxy-l7,8-acyloxy-17amethyl-19-nor-androsteneand the like.

The oxidation of the lla-hydroxy-steroids according to the presentprocess leads as a rule to mixtures of the larlla-epoxides andlfizlla-epoxides in, which mixture depending on whether the rings A andB are cis-linked or trans-linked one or the other kind of isomerpreponderates.

For the conversion of epoxides into the l-dehydrosteroids especially thelarlla-oxido-steroids are suitable.

Hitherto the 1:2-double bond has been introduced either methods. Thepresent process enables the lz2-double bond to be introduced in acompletely novel manner. The 1a:l1m-oxido-steroids obtained by thepresent process can be opened up hydrolytically or acylolytically underthe action of acids to form lZlla-dlOlS, monoacylates or diacylatesthereof or halohydrins. When the steroid used for splitting the oxidecontains an oxo group in position 3 or when such a group is formedduring the splitting, for example from a B-ketal, the correspondingl-dehydro-llahydroxy compounds are obtained directly.

The lzlla-oxides of the compounds having no free or protected oxo groupin position 3 are opened up for example by means of aliphatic carboxylicacids, such as formic acid, acetic acid, propionic acid, trichloroaceticacid, trifiuoroacetic acid, or in the case of a weak acid if of a strongacid, such as sulfuric or para toluenesulfonic acid. These agents yieldabove all monoacylates of the lzll-diols. When the reaction is performedwith a hydrohalic acid, for example hydrogen chloride or hydrogenbromide, in a diluent as glacial acetic acid, dioxane, methanol or thelike, there are obtained 1-halogeno-1la-hydroxy-compounds whereas underthe action of an acylhalide, for example acetyl bromide,

l-halogeno-l la-acyloxy-steroids are formed. In a medium free fromhydroxyl group the main products formed are derivatives of A-l-hydroxy-steroids; for example, boron trifluoride etherate orpara-toluenesulfonic acid in acetanhydride or propionic anhydride yieldsthe M -1- acetates and A -l-propionates respectively.

' When the lazllu-oxide subjected to the scission contains a free orprotected oxo group in position 3, the opening of the oxide is extremelyeasy and occurs, for example, even by simple heating with glacial aceticacid in the presence or absence of sodium acetate or potassium acetate.In this manner the A -3-oxo-1lot-hydroxysteroids are formed. When a free3-oxo-group is present, the scission of the ether ring also takes placeunder basic conditions, for example already by treating with alkalimetal salts of aliphatic carboxylic acids, such as sodium acetate,potassium acetate, potassium propionate and the like. There are alsosuitable alkali metal alcoholates, bicarbonates, carbonates andhydroxides, for example sodium methylate, potassium isopropylate,potassium tertiary butylate, sodium bicarbonate, potassium carbonate,sodium hydroxide and the like; but also alkaline earth metal hydroxides,such as barium hydroxide, calcium hydroxide. Furthermore, there may alsobe used aluminum alcoholates, for example aluminum isopropylate ortertiary butylate, or tertiary aliphatic or cycloaliphatic amines, suchas triethylamine, N-methylpiperidine, N-methyl-morphdine and the like.Scission can also be performed by chromatography on aluminum oxide. Theabove-mentioned bases are used in suitable solvents in which the oxidocompound and also the base is soluble, for example lower aliphaticalcohols, cyclic ethers or aromatic hydrocarbons or mixtures of thesecompounds.

When a A -3-ketal is used as starting material, the protected group inthe 3-position of a resulting A -lzllaoxido-3-ketal can be split by mildacid treatment, for example with para-toluene sulfonic acid in acetone,or by a short warming with dilute acetic acid whereby surprisingly, notthe A -3-ketones are formed-as in the case with compounds not containinga 1:l1ot-oxido groupbut the A -l:1la-oxido-3-ketones. When the latterproducts are subjected to a mild alkaline treatment, for example withalumina, they are converted into the A -3- oxo-l lu-hydroxy compoundswhich in their turn are easily isomerized for example by heating withacetic acid or by prolonged adsorption on alumina, to form thecorresponding A -3-ketones.

As byproducts of the described reaction of Ila-hydroxy-steroids withmetal acylates having an oxidizing action there are obtained9:ll-seco-ll-nor-compounds in varying yield. For example, A-3:ZO-bisethylenedioxylla-hydroxy-pregnene yields A-3-ethylenedioxy-20-oxo- 9:ll-seco-ll-nor-pregnene with simultaneoushydrolysis of the ketal at carbon atom 20. By subsequent treatment withdilute ace-tic acid the 9:ll-seco-ll-nor-progesterone is obtained. The3:20-dioxo-9:ll-seco-ll-nor-pregnane compounds have a progestative,anti-estrogenic, and blood pressure-regulating action.

In contrast to their lot-epimers, the 1p: lle-oxidosteroids, under theinfluence of acids, yield, particularly in the presence of a ketal orcarbonyl function at carbon atom 3, apart from1-dehydro-3-oxo-1la-hydroxysteroids, mainly A-2z3-seco-llu-hydroxy-steroids, the ring A being split up during theformation of the latter compound. For example, lflzlla-oxido-3z20-bisethyIenediOXy-Sapregnane yields on treatment with sulfuric acid inmethanol the methyl ester of A -2:3-seco-11a-hydroxy-20-oxo-5a-pregnane-3-acid. When dilute acetic acid, a mixture of sodiumacetateand glacial acetic acid, or para-toluenesulfonic acid in acetone is usedfor hydrolysis, the corresponding glycol ester is obtained in place ofthe methyl ester. Hydrolysis of A -lt3211ot-OXidO3:20-bisethylenedioxy-pregnene yields in addition to the A-2:3-seco-11ahydroxy-compound also l-dehydro-llot-hydroxy-progesterone.

The 2:3-seco compounds, on treatment with concen trated sulfuric acid,in part yield 1-dehydro-3-oxo-steroid compounds, re-cyclizationoccurring.

Of the 1:11a-0xido steroids of the pregnane series obtainable by theprocess of this invention, those merit special mention which areoxygenated in 3- and 18-position, in particular those which have anlit-positioned carboxylic acid group lactonized with a ZO-hydroxylgroup. Such 3-oxygenated 18:20-lactones of1:11ot-oxido-20-hydroxypreganane-18-acids, as e.g. the 18:20-lactones ofA -3- oxo- 1 a2 11a-oxido-ZOB-hydroxy-pregnene-18-acids or their3-ketals can be converted, after opening up the 1:11aepoxide ring by theprocess of this invention, or by way of the 2:3-seco compoundsmentioned, into the corresponding 1-dehydro-18z20-lactones of20-hydroxy-pregnene-18-acids. Compounds of this kind are suitable asintermediate products for the manufacture of physiologically activel-dehydrocorticoids having an oxygen function in 18-position. Theconversion of the aforementioned l-dehydro-lStZO-lactones of20-hydroxy-pregnene- 18-acids can be illustrated as follows: The18:20-lactone of 3-oxo-1laz2Ofi-dihydroxyed pregnadiene 18 acidobtainable by the process of this invention is converted into the:18-lactone of 3-oxo-115:20 3-dihydroxy-A pregnadiene-18-acid bytreatment of its tosylate with a base, e.g. potassium carbonate, theZO-hydroxyl group of the conversion product dehydrogenated to form the0x0 group, and an acyloxy group introduced in 21-position in per seconventional manner; after ketalization of the 20- oxo group, thecarbonyl groups at carbon atoms 3 and 18 are treated with the quantityof lithium aluminum hydride calculated for the conversion of the lactonegroup in 18:11-position into an 18:1l-cyclosemiacetal group and for thereduction of the 3-oxo-group, after which the 3- hydroxy group isselectively re-oxidized under the conditions of the Oppenauer reaction,and the ZO-ketal group of the resulting product is hydrolyzed under acidconditions. In this manner the l-deyhdro-aldosterone is obtained.

In a similar manner, the 18:20-lactones of A -3-oxo-11a:ZO-dihydroxy-steroid-18-acids obtainable by the process of thisinvention, especially those of the pregnane series, can be converted byselective reduction of the 1:2- double bond, followed by isomerization,into the 18:20- lactones of A -3-oxo-11:20-dihydroxy-pregnane-l8-acidswhich in turn can be converted into the l1B:18-lactones of A-3,20-dioxo-1lfi-hydroxy-pregnene-l8-acids by the method describedabove. These latter products are known intermediates for the manufactureof aldosterone or derivatives thereof.

The following examples illustrate the present process.

Example 1 1.480 grams of A -3:20-bisethylenedioxy-1let-hydroxypregnene(melting at 215-217C.; obtained by ketalising 1lot-hydroxy-progesterone)are added to a stirred suspension previously boiled for 15 minutes of1.5 grams of calcium carbonate and 4.5 grams of lead tetraacetate in cc.of methyl-cyclohexane, and the reaction mixture is refluxed for 18hours, filtered, the filter residue is washed with ethyl acetate andether, the filtrate is shaken once with 40 cc. of potassium iodidesolution of 5% strength, once with 40 cc. of sodium sulfite solution of10% strength and three times with water, dried and evaporated. There areobtained 2.09 grams of a substantially crystalline residue. Onerecrystallization from a mixture of methylene chloride and petroleumether yields 620 mg. of a A -3z20-bisethylenedioxy-laz11a-fiido-pregnenemelting at 203-208 C. Elution of the mother liquors by chromatography onalumina yields another 174 mg. of the same compound which melts at213214 C. after having been twice recrystallized. The infra-red spectrumof the compound contains no absorption bands in the OH and CO regions.Subsequent chromatogram fractions yield 105 mg. of A-3:ZO-bisethylenedioxy-lfi:lla-oxidopregnene melting at 185-188 C. whichis isomeric with the above compound at carbon atom 1. A mixed meltingpoint test of the two isomers produces a very minor depression, buttheir infra-red spectra diifer. chromatography about 50 mg. more ofstarting material can be eluted.

From the fractions eluted with a mixing of petroleum ether and benzene A-3-ethylenedioxy-20oxo-9:ll-secoll-nor-pregnene is isolated. After beingrecrystallized three times from a mixture of methylene chloride andhexane the product melts 148-149 C.; optical rotation [a] =-|-11.2:1. Inthe nuclear magnetic resonance spectrum of the compound, signals occurinter alia at 321, 238, 128, 78, 67 and 47 Hertz units of frequency(obtained in deuterochloroform with tetramethylsilane as internalreference). After hydrolysing the ketal grouping at carbon atom 3 bymeans of para-toluenesulfonic acid in acetone, there is obtained9:11-seco-11-nor-progesterone melting at 8990 C. In the nuclear magneticresonance spectrum of the compound signals occur inter alia at 343, 130,73 (corresponding to 6 protons) and 49 Hertz units of frequency.

Example 2 300 mg of A -3 :20-bisethylenedioxy-1a:lla-oxido-pregnene in12 cc. of acetone are treated with 50 mg. paratoluenesulfonic acid andthe whole is stirred at room tem perature until all has passed intosolution and the solution is kept for 14 hours, diluted with water,cooled to C., and the precipitated A -3:20-dioxo-1a:Ila-oxidopregnene isfiltered off and washed with water. One recrystallization from a mixtureof methylene chloride and petroleum ether yields 95 mg. of the productwhich crystallizes in lustrous flakes and melts at 194-198 C.(uncorrected). The infra-red spectrum of the product displays anabsorption band at 588p. When the acetone is distilled oif the aqueousfiltrate under reduced pressure at about 60 C., the concentratedfiltrate is saturated with sodium chloride and subjected to aconventional extraction with ether-l-methylene chloride (3:1), 132 mg.of a partially crystalline oil are obtained which yields oncrystallization from ether 67 mg. of A-3z20-dioxo-lla-hydroxy-pregnadiene. The melting point, mixed meltingpoint and infra-red spectrum of this product are identical with those ofthe product described in Example 3. The mother liquor contains a mixtureof the aforementioned A -lzlla-ether and lla-hydroxy-diene.

Example 3 50 mg. of A -3:20 bisethylenedioxy pregnene are dissolved withheating in 5 cc. of acetic acid 80% strength, 30 mg. of sodium acetateare added, and the whole is heated for 2 hours at 100 C. The mixture iskept for 15 hours at room temperature, diluted with cc. of water,saturated with sodium worked up with ether-l-methylene chloride (3:1).When the isolated oil (32 mg.) is sprinkled with ether, it crystallizes.Two crystallizations from a mixture of methylene chloride, ether andpetroleum ether yields A -3:20- dlOXO-lloc-hYdIOXY pregnadiene in fineneedles melting at 220-2205 C. Optical rotation [a] =+102.4i0.8 (c.=1.03in chloroform). Absorption maximum at 248 m (e=21,000). The infra-redspectrum of the compound in Nujol contains absorption bands at 2.90,5.85, 6.03, 6.16 and 6.25,a.

- la: 1 ltZ-OXldO- Example 4 100 mg. of A3:ZO-bisethyIenediOXy-Ia:Ila-oxidopregnene are dissolved in 3:5 cc. ofacetic acid of 80% strength by being heated to 60 C., the solution ismaintained for a total of 5 minutes at the same temperature and thenkept for 30 minutes at room temperature. The reaction mixture is dilutedwith water, saturated with sodium chloride and extracted with ether. Theextracts are washed with sodium bicarbonate solution and with By carefulI chloride and water until neutral, dried and evaporated. The crudeproduct is a mixture of A 3 ethylenedioxy-1a:11aoxido 20 oxo pregneneand A -3I20-dlOXO-10t211w oxido pregnene (strong absorption band in theinfrared spectrum at 5.87-5.89p). Subsequent chromatography on aluminayields the former compound in pure form melting at 135-139" C. However,during the chromatography A 3:20 dioxo 1a:11aoxido-pregnene is convertedinto the isomeric A -3:20- dioxo-l1u-hydroxy-pregnadiene melting at172175 C. A :228 ma, E=11,600. Infra-red absorption bands in methylenechloride: 5.87 4, 5.94 1. and 6.24/.L.

Example 5 3.0 g. of dried calcium carbonate and 10.0 g. of predriedlead-IV-acetate in 300 ml. of cyclohexane are heated for 15 minutes atC. with stirring. After that, 3.0 g. of3:ZO-bisethylenedioxy-l1a-hydroxy-5 3-pregnane are added and the mixturestirred for 17 hours while being resulting 0a,,8-UI1S3tLlI3t6d ketoneThe cooled reaction solution is potassium iodide solution, ml. of 10%sodium sulfite solution, and

Chromatographic purification over alumina yields 2.24 g. of pure3:29-bisethylenedioxy-1a,1la-oxido-5fl-pregnane in the form of a foam.In the IR-spectrum of the compound, absorption bands are observed interalia at 7.55,u, 920 9.30,u, 950p, 9.66 t, 1000 1055 11.00',u and11.45,a.

In the same manner the3:20-bisethylenedioxy-1lot-hydroxy-Zl-acetoxy-Sfi-pregnane obtainable byketalization from 3:20 dioxo 11a-hydroxy 2l-acetoxy-Sfi-pregnane mayalso be converted into 3:20 bisethylenedioxy-laz 1 1a-oxido-2 l-acetoxy-5fi-pregnane.

Example 6 3.8 g. of 3:ZO-bisethylenedioxy-llot-hydroxy Six-pregnane areadded to a suspension which has been heated at 100 C. for 15 minutes-0f3.8 g. of calcium carbonate and 12.7 g. of lead-IV-acetate in 380 ml. ofmethylcycl-ohexane, and the whole stirred for 14 hours while beingrefluxed. Another 5.0 g. of lead-IV-acetate then added and boilingcontinued for 3 more hours. in the same manner as from a mixture ofmethylene chloride and petroleum ether yields 1.51 g. of 3:20bisethylenedioxy-ltglla-oxido-5a-pregnane of melting point 203-206 C.Chromatographic purification of the mother liquors yields 1.12 g. of thesame product. [a] :+4.0 (c.=0.75, in CHCI The infrared spectrum showsbands inner alia at 7.30 7.56,u., 8.25 8.41,:t, 855 9.57,u, 10031056,44, 1153,41. and 11-72/L.

The 11ot-hydroxy-3:ZO-diketals of 5a and SB-pregnane, respectively, usedas starting materials in Examples 5 and 6 are obtained from thecorresponding 3a and 36:11adiacetoxy-ZO-oxo compounds by partialhydrolysis of the 3-acetates, oxidation by means of N-bromacetamide tothe 3:20-diketone, ketalization, and subsequent alkaline hydrolysis ofthe Ila-acetate.

Example 7 200 ml. of cyclohexane, 2.0 g. of calcium carbonate, and 7.0g. of lead-IV-acetate are heated to 80 C. for a short while, thentreated with 1.50 g. of A-3-ethylenedioxy-l1whydroxy-17/3-acetoxy-17a-methyl androstene (preparedby partial hydrolysis of A -3-ethylenedioxy- 711o,17fl-diacetoxy-17u-methyl-androstene obtained from A-3-oxo-11a:17B-dihydroxy-17u-methyl "androstene by acetylation andketalization). The mixture is refluxed with stirring for 16 hours.Working up in the usual manner (see Example yields 1.85 g. of acrystalline crude prduct, By crystallization from a mixture of ether andpetroleum ether the pure A -3-ethylenedioXy-1E:11aoxido-17B-acetoxy-17ot-methyl-androstene of melting point 185188 C. is obtained.

An analogous treatment of A -3-ethylene-dioxy-11uhydroxy-17B-acetoxyandrostene with lead-IV-acetate yields a mixture of the two oxidocompounds epimeric at carbon atom 1:A -3-ethylenedioxy-1o:11oand A-3-ethylenedioxy-lfi: 1 lu-oxid-o-17fi-acetoxy-androstene.

Example 8 9.0 g. of 18:20-lactone of A -3-ethylenedioxy-1lo:20;8-dihy-droxy-pregnene-18-acid are stirred into a suspension, heated to 100C., of 9.0 g. of calcium carbonate and 30.0 g. of lead-IV-acetate in 900ml. of methylcyclohexane and the mixture boiled under reflux. After 1hour another 10.0 g. of lead-IV-acetate and 5.0 g. of calcium carbonateare added, and after 13 hours another 10.0 g. of lead-IV-acetate. Aftera total of hours, the reaction is stopped and the product worked up.There are obtained about 12 g. of an oily product which is resolved intofour components by chromatography over alumina (activity II).

Yields of 1 to 2% are obtained of the 18:20-lactone of A 3 ethylenedioxy11 oxo B hydroxy pregnene- 1*8-acid. The following compounds aresubsequently separated: an about 15% yield of the 18:20-lactone of M3-ethylenedioxy 9:11 seco 11 nor 20B hydroxypregnene-lS-acid of meltingpoint 186190 C. which is converted by deketalization into the18:20-lactone of A 3 oxo 9:11 seco -11 nor 2013 hydroxypregnene-18-acid;a 20-25% yield of the 18:20-lactone of A 3 ethylenedioxy 1112110 oxido203 hydroxypregnene-18-acid of melting point 160 C. (bands in the IRspectrum at 5.72;, 6.95;, 7.30;, 7.50;, 7.70;, 8.75;, 8.86;, 9.00;,9.25;, 9.62;, 9.80;, 10.03;, 10.35;, and 10.53;), and an about 20% yieldof 18:20-lactone of A 3 ethylenedioxy 152110 oxido 20Bhydroxypregnene-18-acid of melting point 205-209 C. (bands in the IRspectrum at 5.70;, 6.92;, 7.30;, 7.45;, 7.68;, 8.20;, 8.80;, 9.02;,9.20;, 9.80;, 10.18;, 10.55;, 10.75; and 10.95;).

Example 9 In a manner analogous to that described in the precedingexample, there are obtained from 3fi-acetoxy-1lahydroxy-5u-spirostaneand 3;8-acetoxy-1lu-hydroxy-cholestane with lead-IV-acetate3p-acetoxy-1g:llot-oxido-iaspirostane and3B-acetoxy-1g:lla-oxidO-Soc-cholestane respectively.

Example 10 210 mg. of 3:20-bisethylenedioxy-1o:11a-oxido-5flpregnane aredissolved in 20 ml. of glacial acetic acid,

treated with 200 mg. of crystalline sodium acetate, and refluxed for twohours. The reaction solution is diluted with benzene and evaporatedunder reduced pressure. The residue is dissolved in water and ether, andthe organic layer washed neutral with sodium bicarbonate and water. Theethereal solution is dried and evaporated under reduced pressure. Itgives a quantitative yield of l-dehydro-3 :20-dioxo-11a-hydroxy-5B-pregnane. The product is recrystallized twice from methylenechloride+petroleum ether and then melts at 198199 C. M1 +-174.5- :1.2(chloroform). In the IR spectrum bands at 2.75-2.90;, 5.88;, 5.98;,6.25;, 7.22;, 7.30;, 7.40;, 8.20;, 8.66;, 9.00;, 9.50;, 10.18;, and11.88;.

Example 11 200 mg. of 3:ZO-bisethylenedioxy-la:1la-oxido-Sfipregnane, 20ml. of glacial acetic acid and 200 mg. of crystalline sodium acetate areheated at 80 C. for 4 minutes. The reaction mass is then diluted withbenzene, and the solvent expelled under reduced pressure. Working up asin Example 10 yields 183 mg. of3-ethylenedioxy-la:11ot-oxido-20-oxo-5B-pregnane which after beingrecrystallized from a mixture of methylene chloride and petroleum ethermelts at 169170 C. [Mg -+938: 1.0 C. (c.=1.'027, in chloroform). (Bandsin the IR spectrum inter al-ia at 5.88;, 7.25;, 7.40;, 7.50;, 7.65;,8.50;, 9.02;, 9.20;, 9.30;, 9.65;, 9.98;, 10.55;, 11.00;, 11.45; and11.75;)

Example 12 150 mg. of 3:20-bisethylenedioxy-1fi:lla-oxido-5apregnane aredissolved in 10 ml. of acetone and, after the addition of 25 mg. ofpara-toluene-sulfonic acid monohydrate, allowed to stand at roomtemperature for 18 hours. The solution is neutralized with a few dropsof saturated sodium bicarbonate solution, concentrated under reducedpressure at 40 C., diluted with ether, and washed three times withwater. On evaporation of the solvent there are obtained 138 mg. ofcrystalline glycol ester of 2.3 seco A 11o hydroxy 20 oxo 5; pregnene-3-acid of melting point 103104 C. After being recrystallized twice froma mixture of methylene chloride and petroleum ether, the compound meltsat 105-106 C. [a] :+67.0i1.2 C. (c.=l.0, in CHCl The IR spectrumexhibits inter al-ia bands at 2.82;, 5.78;, 5.87;, 6.15;, 7.38;, 8.50;,9.81; and 10.80;. The same product is obtained by treating3:20-bis-ethylenedioxy-1B:11ooXido-Sa-pregnane with glacial aceticacid-l-sodiurn acetate or dilute acetic acid.

By hydrogenation of 150 mg. of A -glycol ester in rectified alcohol withpalladium black and recrystallization from a mixture of ether and hexanethere are obtained 130 mg. of the glycol ester of2:3-seco-11ahydroxy-20-oxo-Sa-pregnane 3 acid. Double melting point at92 C. and 107-l08 0; optical rotation [a] "=+43.2:1.8 (c.=0.560).

Example 13 400 mg. of 3:20-bisethylenedioxy-1B:11oc-oxido-5apregnane aresuspended in 8 ml. of methanol and, after the addition of 0.02 ml. ofconcentrated sulfuric acid, allowed to stand at 20 C. for 15 minutes.The mixture is shaken from time to time. The solution is thenneutralized with saturated sodium bicarbonate solution, extracted withether, the ethereal layer washed nuetral with water, dried andevaporated. For complete cleavage of the C-20 ketal, the resulting crudeproduct is dissolved in 2 ml. of glacial acetic acid, treated with 0.5ml. of water, and heated to 60 C. for 10 minutes. The subsequent workingup yields 245 mg. of the methyl ester of 2:3-seco- A-l1a-hydroxy-ZO-oxo-5a-pregnene-3-acid. After being recrystallized froma mixture of ether and petroleum ether, the compound melts at 110 C.(The IR spectrum exhibits bands at 2.81;, 5.78;, 5.90;, 6.5;, 7.23;,7.30;, 7.36;, 8.15;, 8.40;, 8.55;, 8.65; and 10.80;) Optical rotation[a] =+77.3i1 (c.=0.818 in chloroform). The same compound is obtainablealso from the glycol ester described in Example 12 by hydrolysis to form2:3- sec0-A 1loc-hydr0Xy-2O-oX0-5ot-pregnene-3acid and subsequentesterification by means of diazomethane.

By ozonization of the methyl ester in glacial acetic acid solution atroom temperature and subsequent afteroxidation withchromium-(VI)-oxide+sulfuric acid in acetone there is obtained in goodyield the 1:11-lactone of the S-methyl ester of2z3-seco-2-nor-11u-hydroxy-20- oxo-5u-pregnane-l:3-diacid. The compoundmelts at 209-210" C. after being recrystallized three times from amixture of methylene chloride and hexane. Optical rotation [a] =+45.9i1(c.=0.980 in chloroform).

Example 14 200 mg. of A 3ethylenedioxy-1E:11-u-oxido-17fiacetoxy-17a-methyl-androstene, dissolvedin 30 ml. of absolute tetrahydrofuran, are added dropwise with stirringand cooling to a suspension of 120 mg. of lithium aluminum hydride in 25ml. of tetrahydrofuran. The reaction mixture is then refluxed for 2hours with stirring, and worked up as usual. There is obtained the crudeA -3- ethylenedioxy-lg:lla-oxido-l7fi-hydroxy 17a methylandrostene.

Example 150 ml. of absolute benzene, 1.50 grams of dried calciumcarbonate and 5.0 grams of lead-IV-acetate freed from excess acetic acidin vacuo are boiled for a short time; 100 gram of A-3-ethylenedioxy-lla-hydroxy-17/3- acetoxy-l7a-methyl-l9-nor androstene(prepared from 110: hydroxy-l9-nor-methyltestosterone) is then added andthe whole boiled under reflux for 18hours with stirring. The reactionsolution which still contains excess lead-IV-acetate is filtered offfrom the inorganic portion and worked up as described in the precedingexamples. 1.25 grams of crude cyclisation mixture are obtained whichcontains in addition the oily reaction product of the solvent. Bychromatography on aluminnum oxide there is obtained in yield purse A -3-ethylenedoxy-lazlla-oxdo-17fl-acetoxy-17a methyl-19 nor-androstene whosebands in theinfrared and nuclear resonance spectra correspond to theexpected as regards position and intensity.

Example 16 200 mg. of A --3ethylenedioxy-luzllwoxido-lfliacetoxy-l7a-methyl-l9-nor-androstenedissolved in m1. of absolute tetrahydrofuran are added dropwise withcooling to a stirred suspension of 200 mg. of lithium aluminw numhydride in 95 ml. of tetrahydrofuran. When the addition is complete,cooling is replaced by. an oil bath and the reaction mixture boiledunder reflux for'l hour with stirring. Working up in the customarymanner yields 157 mg. of A -3-ethylenedioxy-la:lla-oxido-UB-hydroxy-17a-methyl-l9 nor androstene which may be subjected tohydrolysis either after recrystallization or directly.

By heating A 3 ethylenedioxy-laz1lot-oxido-17Bhydroxy-l7a-methyl-19nor-androstene for a short time (5 minutes) at C.with acetic acid of 66% strength and by subsequent working up there isobtained A -3-oxola: lla-oxido-17fi-hydroxy-l7a-methyl 19 norandrostene.

Subsequent treatment with a mixture of glacial acetic acid and sodiumacetate under normal conditions leads to the splitting of the ether ringwith simultaneous aromatisation of ring A and formation of Afiillotil'lfitrihydroxy-l7a-methyl-oestratriene which may becharacterized by its infrared, ultaviolet and nuclear magnetic resonancespectra.

What is claimed is:

1. A compound of the formula CHg-R in which R, is a member selected fromthe group consisting of 0x0, lower alkylenedioxy, hydrogen and hydroxyand hydrogen and acyloxy, R is a member selected from the groupconsisting of an (repositioned hydrogen and a ,H-positioned hydrogen,each of R and R is a member selected from the group consisting ofhydrogen, hydroxy and acyloxy and R is a member selected from the groupof hydroxy and acyloxy, and the dehydro compound thereof containing adouble bond extending from carbon atom 5, said acyloxy radicals beingderived from acids selected from the group consisting of loweraliphatic, monocyclic cycloaliphatic, monocyclic carbocyclic arylloweraliphatic, monocyclic carbocyclic aromatic, monocyclic heterocyclicaromatic monoand dicarboxylic acids, lower alkane and monocycliccarbocyclic aromatic sulfonic acids.

3. A member selected from the group of a compound of the formula inwhich R is a member selected from the group consisting of 0x0, loweralkylenedioxy, hydrogen and hydroxy and hydrogen and acyloxy, R is amember selected from the group consisting of an Ot-POSltlOIled hydrogenand a fl-positioned hydrogen, R is a member selected from the group of0x0, lower alkylenedioxy, hydrogen and fl-hydroxy, hydrogen andB-acyloxy, methyl and Er-hydroxy and methyl and fi-acyloxy and R is amember selected from the group consisting of hydrogen and methyl, andthe dehydro compound thereof containing a double bond extending fromcarbon atom 5, said acyloxy radicals being derived from acids selectedfrom the group consisting of lower aliphatic, monocyclic cycloaliphatic,monocyclic carbocyclic aryl-lower aliphatic, monocyclic carbocyclicaromatic, monocyclic heterocyclic aromatic monoand dicarboxylic acids,lower alkane and monocyclic carbocyclic sulfonic acids.

4. A compound of the formula 5 "Fij a-positioned and the S-dehydrocompound thereof.

8. 3fi-acetoxy-15: lla-oxido-Sa-spirostane.

9. 3B-acetoxy-15: 11a-oxido-5m-cholestane.

10. 3:20-bisetl1ylenedioxy-1:Ila-oxide 21 acetoxy- SB- regnane.

11. A 18:20-lactone of a pregnadiene-lB-acid.

12. A -3-oxo-11a-hydroXy-l7fl-acetoxy-17a androstadiene.

13. 2: 3-seco-A -l 1a-hydroxy-20-oxo-pregnene-3-acid.

14. Glycol ester of 2:3 seco-A -lIa-hydroxy-ZO-oxopregnene-3-acid.

15. Glycol ester of 223-8660-1loc-l'lYdIOXY-ZO-OXO-Sapregnane-3-acid.

16. M3 :20-dioxo-9: 1 l-seco-l l-nor-pregnene.

17. 18:20 lactone of A -3-oxo-9:l1-seco-11-nor-2Oflhydroxy-pregnene- 18-acid.

18. lzll-lactone of 3-methyl ester of 2:3-seco-2-norl1a-hydroXy-20-oxo-5wpregnane-1 3-diacid.

A -3-oxo-1laz20-dihydroxymethyl- References Cited by the Examiner LEWISGOTTS, Primary Examiner.

L. H. GASTON, Examiner.

IRVAN MARCUS, M. L. WILLIAMS, H. FRENCH,

Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,316,253 April 25, 1967 Albert Wettstein et a1.

n the above numbered patthat error appears i ent should read as It ishereby certified that the said Letters Pat ent requiring correction andcorrected below.

Column 10, line 61, before Signed and sealed this 28th day of November1967.

(SEAL) Attest:

EDWARD J. BRENNER "sulfonic" insert aromatic -a

1. A COMPOUND OF THE FORMULA